Delivery of every aspect of care by all clinical and non-clinical departments in the UK's NHS is being reassessed and fundamentally reorganised in the expectation of an imminent surge of patients with covid-19. 1 Modelling of the outbreak assumes an infection fatality ratio of 0.9% and a hospital admission rate of 4.4%, with 30% of those admitted requiring critical care or extracorporeal membrane oxygenation. 2 3 The increased demand on healthcare services will be compounded by the apparent increased risk of infection among healthcare workers, 4 and staff absences because of illness or self-isolation may be as high as 20%. 11 The government has made recommendations for case isolation, social distancing, and household quarantine intended to reduce the peak of the epidemic and the resulting pressure on NHS hospitals. 5 6
Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.